Members of the 3-hydroxy-4-oxo-1,4-dihydropyridine class are well known for their ability to chelate iron in physiological environments and have been reported to be useful in treating iron related disorders such as thalassaemia and anemia (see U.S. Pat. Nos. 4,840,958; 5,480,894; 5,688,815; Liu et. al, J. Med. Chem. 1999, 42(23), 4814-4823).
Derivatives of 3-hydroxy-4-oxo-1,4-dihydropyridine-2-carboxamide (formula I) are bidentate iron chelators with potential for oral administration (Bioorganic & Medicinal Chemistry 2001, 9, 563-567; Current Medicinal Chemistry 2003, 10, 983-995; U.S. Pat. No. 6,335,353 and NZ 529657). Selected compounds of formula I have been orally tested using an iron mobilization efficacy assay in the rat (see Table 3 of U.S. Pat. No. 6,335,353 and example 12 of NZ 529657). Such compounds of formula I are chelators possessing high pFe3+ values and hence show great promise in their ability to remove iron under in-vivo conditions.
There are several reported syntheses of 3-hydroxy-N,1-disubstituted-6-methyl-4-oxo-1,4-dihydropyridine-2-carboxamides. The starting material for the synthesis of the acid (1) is reported in U.S. Pat. No. 6,472,532 and shown in scheme 1:

In the first approach described in U.S. Pat. No. 6,335,353, a representative compound, 3-hydroxy-N,1,6-trimethyl-4-oxo-1,4-dihydropyridine-2-carboxamide (CP502; (5)) has been prepared by the method described in examples 45 to 48, 53 and 58 of U.S. Pat. No. 6,335,353. The 2-carboxyl derivative (1) is prepared from allomaltol in three steps. The derivative (1) reacts with dicyclohexyl-carbodiimide (DCC), 2-mercaptothiazoline and 4-dimethylaminopyridine to give 3-(2-carbonyl-3-benzyloxy-6-methyl-4(1H)-pyran-2-yl)-1,3-thiazolidine-2-thione (2) which is subsequently reacted with methylamine (MeNH2) in tetrahydrofuran (THF) to give 3-benzyloxy-6-methyl-4(1H)-pyran-2-yl)-2-carboxy-(N-methyl)-amide (3). The 3-benzyloxy-6-methyl-4(1H)-pyran-2-yl)-2-carboxy-(N-methyl)-amide (3) is converted to 1,6-dimethyl-3-benzyloxy-4(1H)-pyridinone-2-carboxy-(N-methyl)-amide (4) with methylamine in alcohol, in particular methanol (MeOH). The 3-benzyloxy derivative (4) was deprotected with hydrogenation using Pd/C in ethanol as illustrated in Scheme 1 to give CP502 (5).
In a second approach reported in US 6,476,229, compound (1) is reacted with 1,1′-carbonyl diimidazole (1,1′ -CDI) and methylamine to give the compound (4) directly (step e of scheme 1). This approach reduces the two step conversion of (1) to (4) into a single process step. The 3-benzyloxy derivative (5) was deprotected with hydrogenation using Pd/C in ethanol as illustrated in Scheme 1 to give CP502 (5).
In a third approach described in NZ 529657, the method in step e of scheme 1 was modified to prepare 1-cyclopropyl-3-hydroxy-6-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid methylamide (Apo6619) (see scheme 2 below). Acid (1) was reacted with 1,1′-carbonyldiimidazole to give the amide (3). Subsequent reaction of (3) with cyclopropylamine in alcohol affords compound (6) in moderate yield. The 3-benzyloxy derivative (6) was deprotected with hydrogenation using Pd/C in ethanol or methanol to give compound Apo6619.

In general, all three approaches share the amide intermediate (3A) (Scheme 3). Insertion of either an alkylamine or cycloalkylamine R′NH2 (R′=alkyl or cycloalkyl) into the 3-benzyloxy-6-methyl-4-oxo-4H-pyran-2-carboxylic acid methylamide affords the 3-hydroxy-4-pyridinone (5A). However, such insertion reaction proceeds in less than 60% yield and generates by-products when the R′NH2 is a hindered alkylamine or cycloalkylamine, creating problematic isolation of the product by crystallization at the manufacturing scale.

Whilst there exists a number of reaction routes for the formation of 4-oxo-1,4-dihydropyridine-2-carboxamides analogues and derivatives thereof, known processes do not provide sufficient yield for industrial application and further, result in the need of toxic and/or hazardous waste disposal.
It is therefore an object of the present invention to provide an improved process for the production of 1-cyclopropyl-3-hydroxy-N,6-dimethyl-4-oxo-1,4-dihydropyridine-2-carboxamide and 3-(benzyloxy)-1-cyclopropyl-N,6-dimethyl-4-oxo-1,4-dihydropyridine-2-carboxamide from 3-(benzyloxy)-1-cyclopropyl-6-methyl-4-oxo-1,4-dihydropyridine-2-carboxylic acid, which can be prepared at yields sufficiently high for industrial application.